tbuckley/cabot-search huggingface dataset:
The clinical and genomic characteristics of MSI-h/dMMR lung cancer.
Authors: Jianwen Qin, Dongsheng Shi, Yan Yin, Bin Liu, Lei Wang, Tingting Sun, Qin Zhang, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e21142 Background: Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) have been confirmed to be positively predictive biomarkers for immune checkpoint inhibitors (ICIs), especially in colorectal cancer and endometrial cancer. Numerous studies about molecular characteristic or clinical trails of MSI-H/dMMR have been achieved or ongoing. However, there are few researches of MSI-H/dMMR in lung cancer which has the highest morbidity in malignant tumors. Here, we explored clinical and genomic characteristics of MSI-H/dMMR lung cancer. Methods: We retrospectively analyzed 4996 lung cancer patients with available tissue NGS data. Microsatellite status was decided by MSI score which was tested by NGS combined with bioinformatics algorithms (MSI score &lt; 0.05: MSS; MSI score &gt; 0.15: MSI-H). In the absence of MMR IHC, dMMR was alternatively defined that DNA mismatch repair genes, including MLH2, PMS2, MSH2 and MSH6, had pathogenic or likely pathogenic mutations based on the American College of Medical Genetics and Genomics (ACMG) guidelines. RNA data of 552 lung cancer patients from The Cancer Genome Atlas (TCGA) was obtained to analyze immune microenvironment. Results: Of 4996 lung cancer patients, 58 (1.16%) patients were identified to be MSI-H/dMMR with a median age of 65.5 years old, of which 2.80% (9/322) patients were squamous carcinoma, significantly higher than adenocarcinoma 1.06% (30/2839) (p &lt; 0.05). In MSI-H/dMMR, 8 (13.89%) patients were MSI-H, 41 (70.69%) patients were dMMR and 9 patients were both MSI-H and dMMR (15.52%). Compared with MSS patients, MSI-H/dMMR patients had more frame shift mutations. Moreover, it more often happened in dMMR than MSI-H that there were multiple mutations in one gene, which was indicated by Multi-Hit. Further exploration found that MSI-H/dMMR tumors had higher tumor mutation burden (TMB) than MSS (p &lt; 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in MSI-H/dMMR tumors. Activated CD4 memory T cell and CD8 T cell were more abundant in MSI-H/dMMR tumors. Conclusions: We analyzed clinical and genomic characteristics of MSI-H/dMMR lung cancer for the first time. Our data showed that MSI-H/dMMR was found in 1.16% lung cancer patients and more likely to occur in squamous cell lung carcinoma. MSI-H/dMMR in lung cancer was associated with higher TMB and may well enhance anti-tumor immunity.
A mixed-methods study of healthcare provider perspectives on the barriers to enrollment of minority patients on cancer clinical trials.
Authors: Yonghun Kim, Mary O'Shea, Gladys Asiedu, Katharine Andress Rowe Price, Rahma M. Warsame
Journal: Journal of Clinical Oncology (2022)

e18544 Background: Underrepresented minority (URM) patients continue to make up a small percentage of patients treated on cancer clinical trials (CCTs), thus perpetuating health care disparities. Research indicates that engagement of healthcare staff is critical for successful recruitment. Our study sought to better define barriers to minority recruitment to CCT from the research staff perspective. Methods: Semi-structured qualitative interviews were conducted of key stakeholders for CCT enrollment, including clinical research coordinators (CRCs), principal investigators (PIs), and treating clinicians. Questions for the healthcare team explored their experiences caring for URM patients with specific inquiry into the barriers of enrollment/retention and the processes or resources required to better meet patient needs. Results: All hematology and oncology staff at Mayo Clinic Cancer Center were invited to participate via email. Of the 28 who consented, 13 were male (46%), 15 female (54%), and 21% non-white (3 Asian, 2 Hispanic, 1 Black). Of the 19 PIs, 9 were Professors (47%), 5 Associate professors (26%), and 5 Assistant professors (26%). The additional 9 interviewees were CRCs. Select themes with representative quotes and proposed actions can be seen in Table. Conclusions: Recommendations for CCT accrual include accelerating efforts to address workforce diversity gaps, engaging in community outreach, optimization of CCT participation through collaborative care, incentivizing trial participation, and creating flexibility in eligibility criteria.[Table: see text]
Does timing of Immune checkpoint inhibitors (ICIs) administration in first line Metastatic Renal Cell Carcinoma (mRCC) have impact in survival outcomes?
Authors: Javier Molina-Cerrillo, Ignacio Ortego, Alvaro Pinto, Teresa Alonso-Gordoa, Francesco Massari, Gaetano Aurilio, Sebastiano Buti, Matteo Santoni, Enrique Grande
Journal: Journal of Clinical Oncology (2022)

e16512 Background: Recent data in metastatic melanoma patients shows that time-of-day infusion of ICIs may directly impact on the efficacy based on the dependence of the adaptive immune system on circadian rhythm. ICIs either as single agents or in combinations, are now considered the backbone systemic treatment of mRCC pts. There is a strong biological rational showing that “Clock genes”, particularly PER2, TIMELESS and TIPIN have an altered expression in RCC compared with normal tissue. We conducted a retrospective analysis in pts with mRCC receiving ICIs-based therapies in order to determinate whether timing of ICIs administration has an impact on survival outcomes. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 3 in Italy to describe the outcome of all pts who received ICIs-ICIs or ICIs-TKI treatment for the first line setting of mRCC in daily standarc practice related to the timing of administration. We selected 16.30h as the time-limit and identified the pts receiving more than 20% of the treatment infusion after that time. Pts were treated and evaluated according to institutional local guidelines. Pts characteristics, efficacy and treatment-related toxicities were gathered. A Cox regression analysis was conducted to explore the association of baseline variables. Results: From 2019, 61 pts received either Nivolumab/Ipilimumab (N = 46, 75.4%) or pembrolizumab/axitinib (N = 15, 24,6%) for the upfront mRCC treatment. 52 (85.2%) pts (17 ICI+TKI and 25 ICI+ICI) received less than 20% of the ICIs combination treatment infusion after 16.30h compared with 9 (14.8%) pts (3 ICI+TKI and 6 ICI+ICI) who received more than 20% of the treatment infusion after 16.30h. Median follow up was 14.6 months (m). Pts who received most treatment before 16.30h had a significantly longer median PFS compared with those pts with the latest administration (12.3 vs 5.6m; HR 2.28: 95%CI 1.1-5.15; p = 0.048). Overall Survival (OS) data were immature but showed a tend to a better survival for those patients with earlier infusion administration (HR 2.33 p = 0.16). Corticosteroids concomitant administration or immune-related adverse events did not seem to have an impact on these results. Conclusions: Consistently to the melanoma findings, we also identified a potential survival impact from timing of IO administration in mRCC pts receiving ICIs-based combinations in first line treatment. Despite these promising results, there are study limitations such as number of patients and heterogeneous treatment groups. Larger prospective and randomized data are needed to assess the robustness of this hypothesis in the clinic.
Performance and clinical utility of homologous recombination deficiency (HRD) determined by genome-wide loss of heterozygosity (LOH).
Authors: Chien-Feng Li, Shu-Jen Chen, Kien Thiam Tan, Ka-Po Tse, Woei-Fuh Wang
Journal: Journal of Clinical Oncology (2022)

e15025 Background: Homologous recombination deficiency (HRD) status plays an important role in identifying patients with ovarian cancer likely to benefit from Poly (ADP-ribose) polymerase inhibitor (PARPi) and platinum-based chemotherapies. Methods: ACTHRD is an NGS-based assay was designed to determine the homologous recombination deficiency (HRD) status based on the extent of genome-wide loss of heterozygosity (gLOH) and the detection of BRCA1/2 genes alteration. More than that, ACTHRD also assesses the mutational status of 22 homologous recombination repair (HRR) genes. We evaluated the performance and clinical utility of the ACTHRD and compared it with the FDA-approved companion test myChoice CDx. Results: Of the 36 specimens assayed, 24 were determined to be HRD, and 10 were determined to be homologous recombination repair proficient (HRP). The results showed high concordance with myChoice CDx with 100% positive percent agreement (PPA) and 90.91% negative percent agreement (NPA) in the HRD status estimation. Except one case showed HRD in the ACTHRD but showed homologous recombination proficiency (HRP) in the comparator panel. This patient responded to platinum-based chemotherapy and remained disease-free for up to 56 months. One BRCA1/2 wild-type patient was identified as HRD by myChoice CDx but not eligible for ACTHRD test due to low tumor cellularity experienced refractory 13 months after the initiation of the treatment. We further found that ovarian cancer patients identified as HRD by ACTHRD had significantly prolonged progression-free survival (PFS) after being treated with platinum-containing chemotherapies, regardless of BRCA1/2 mutational status. Conclusions: The ACTHRD assay provides high accuracy for identifying deleterious BRCA1/2 alterations and determining the HRD status of ovarian cancers. The analytical robustness of the test has been validated and indicates its suitability for clinical use. Notably, the prognosis data demonstrates that ACTHRD can predict eligible patients for platinum-based chemotherapy and may also be sensitive to PARPi treatment.
Using G8 and carg toxicity score to predict emergency room (ER) visits, hospitalizations, and mortality in older patients with newly diagnosed cancer.
Authors: Amit Arora, Hongxin Sun, John L. Shaia, Tatjana Kolevska, Dinesh Kotak, Kate Belohlav, Grant Richard Williams, Raymond Liu
Journal: Journal of Clinical Oncology (2022)

12055 Background: ASCO and NCCN guidelines recommends Geriatric Screening (G8) and CARG chemotherapy toxicity tool assessment for all older patient before receiving chemotherapy as high risk G8 (&lt; 14) and CARG (≥10) are associated with increased chemotherapy toxicities. We conducted a pilot to understand predictors of high risk G8/CARG and if high risk G8/CARG can predict ER/hospitalization and mortality in community-based Oncology clinics in Kaiser Permanente Northern California. Methods: G8 and CARG were administered to all patients ≥65 years with newly diagnosed cancer from 5/1/21 to 12/31/21. Patients were followed for at least 30 days after assessment for ER/hospitalization and mortality. The median follow-up days from referral to ER/hospitalization was 96 days (range 0-273 days). Chi-Square tests were applied for G8/CARG risk category with demographic and utilization variables. Cox proportional-hazards models were performed to see the association between G8/CARG score and days from referral to ER/hospitalization, and days from referral to death, adjusted for age, sex, race, and cancer type. Results: During this pilot 1082 patients (52% female) completed G8, and 516 patients (57% female) completed CARG. Percentage of patients with high risk G8/CARG increased with each decade (G8: &lt; 70 yrs (58%), 70-79 (63%), 80-89 (90%), ≥ 90 (100%); p &lt; 0.001); (CARG: &lt; 70 yrs (19%), 70-79 (43%), 80-89 (65%), 90 and above (81%); p &lt; 0.001). More men than women had high risk CARG (48% vs. 39%, p = 0.012). Ethnicity was not associated with high risk G8 / CARG. Upper GI cancers (UGI) were associated with highest proportion of patients with high risk G8 (88%) and CARG (58%) whereas breast cancer (BC) had the lowest proportion of patients with high risk G8 (46%) and CARG (14%); p &lt; 0.001. In the adjusted G8 model for ER/hospitalization, high risk G8 vs low risk (HR 1.58, CI 1.23-2.03, p = 0.0003) was related to ER/hospitalization. In the adjusted CARG model for ER/ hospitalization, high risk CARG vs low risk (HR 2.42, CI 1.37-4.29, p = 0.0024) and medium risk CARG vs low risk (HR 2.17, CI 1.23-3.83, p = 0.0074) were related to ER/hospitalization. In the adjusted G8 model for mortality, high risk G8 vs low risk (HR 4.52, CI 2.28-8.97, p &lt; 0.0001) were related to mortality. In the adjusted CARG model for mortality, high risk CARG vs low risk (HR 3.92, CI 1.21-12.74, p = 0.023) and medium risk CARG vs low risk (HR 1.59, CI 0.48-5.33, p = 0.45) were related to mortality. Conclusions: This community-based pilot shows that increasing age is associated with high risk G8 / CARG. G8 and CARG assessment at the time of initial cancer diagnosis can predict early ER/hospitalization and mortality in older adults with cancer and should be included as a part of initial assessment.
Systems biology basis of permanent tumor regression with normal tissue protection: Experimentally validated signaling pathway framework.
Authors: Bindu Kumari, Chandrasekhar Sakode, L. Raghavendran, Prasun Kumar Roy
Journal: Journal of Clinical Oncology (2022)

e15066 Background: Clinicians generally deal with malignant tumors in progression phase only, but there is a reverse complimentary process, namely permanent spontaneous regression of tumors, a well-known phenomenon occurring across human populations at 22%-46% rate (Scandinavian and Wisconsin Screening Registries: 0.33 million and 2.95 million populace respectively; Lancet Oncol.12: 1118-24, 2011; J.Nat.Cancer.Inst.36: 37-47, 2006). Probing such a phenomenon can illuminate how one can induce a permanent regression process on human tumors therapeutically. Here we develop a systems biology approach for this process, that we validate by experimental findings. Methods: Mathematical System Biology Formulation: For permanent tumor regression, we develop a coupled differential equations-based cell kinetic analysis, keeping normal tissue protected. Thereby, we mathematically model the temporal variation of the level of three essential tumor-lysis components: DNA replication-blockade, Antitumor Lymphocyte, Cytokine interleukin-2. Experimental Investigation: We investigate the temporal process of spontaneous tumor regression of melanoma (in Liebechov pigs) and analyze the microarray signal using IPA platform Gene expression signature: Using IPA analysis, we find the signaling pathways associated with the permanent tumor regression. Results: Mathematical System Biology Formulation: We find the temporal behavior of tumor-lysis components are: (1) DNA replication-blockade activation: Unimodal inverted U function (2) Antitumor Lymphocyte activation: Bimodal M function; (3) Interleukin-2 activation as Stationary step function. Experimental findings: Our microarray analysis gives temporal pattern of gene-expression levels corresponding to above three components: G2/M DNA damage checkpoint regulation (genes CCNB1, CDC2), Chemokine signaling activation - Interleukin 2 ( GRB2, PIK3CG), T Lymphocyte Receptor Signaling (CCR5, PRF1). These three temporal components respectively show Unimodal, Bimodal, and Stationary activation. Validation: We show that the three mathematically-derived temporal activation functions are well corroborated by corresponding experimental temporal pathway activation data (Smirnov-Kolmogorov statistical test satisfied; α = 5%). Conclusions: A novel tri-phasic activation of three antitumor signaling pathways (DNA blockade, Interleukin 2, Cytotoxic T cell) can permanently regress melanoma tumor in the experimental setting if the pathways are activated at different time points and not simultaneously; These temporally orchestrated patterns are much different from conventional chemotherapy/ immunotherapy protocols where the temporal activations are simultaneous and empirically chosen. Optimal temporal profiling of administration of antitumor agents is thus crucial from a therapeutic standpoint.
EA2201: An ECOG-ACRIN phase II study of neoadjuvant nivolumab plus ipilimumab and short course radiation in MSI-H/dMMR rectal tumors.
Authors: Kristen Keon Ciombor, Sung Chul Hong, Cathy Eng, Xin Yao, May Thet Cho, Y. Nancy You, Prajnan Das, Anuradha Bapsi Chakravarthy, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2022)

TPS3644 Background: Trimodality therapy including chemoradiation, chemotherapy and surgical resection is standard for patients with T3-4 and/or node-positive (N+) rectal adenocarcinomas. Pathologic complete response (pCR) rates after neoadjuvant chemoradiation approach 15% in all-comers and 27% in patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) rectal cancer. Additionally, preclinical data suggest that hypofractionated radiation (large dose per fraction) may enhance immunogenicity. Given high response rates to immunotherapy in MSI-H/dMMR early stage and metastatic colorectal cancer (CRC), we hypothesized that neoadjuvant nivolumab plus ipilimumab and short course radiation in locally advanced MSI-H/dMMR rectal cancer (LARC) would result in increased pCR rates. Methods: EA2201 (NCT04751370) is an NCTN phase II clinical trial for patients with treatment-naïve locally advanced (T3-4Nx or TxN+) rectal adenocarcinoma that is dMMR or MSI-H. Patients receive nivolumab (480 mg) and ipilimumab (1 mg/kg) every 28 days for 2 cycles, followed by short course radiation (5 Gy x 5 fractions; total 25 Gy) and an additional 2 cycles of nivolumab and ipilimumab prior to disease reassessment and TME. The primary endpoint is pCR at TME. Secondary endpoints include 5-year disease-free survival, overall survival, treatment-related toxicities, and sphincter preservation rate for low-lying tumors. This study has a single-arm, two-stage design; a pCR rate of 50% or more will be taken as evidence of promising activity in this patient population. We plan to enroll 31 patients, with accrual currently ongoing. Clinical trial information: NCT04751370.
A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Ulka N. Vaishampayan, Marianne Keessen, Elisabeth I. Heath, Robert Dreicer, Tomas Buchler, Péter Ferenc Árkosy, Tibor Csoszi, Pawel J. Wiechno, Denis Kholtobin, Evgeny Kopyltsov, Neal D. Shore, Aleander Nosov, Sergey Orlov, Alexey Plekhanov, Maria Smagina, Sergey Varlamov, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2022)

5016 Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in patients (pts) with mCRPC. ModraDoc006 is an oral formulation of docetaxel. To enhance bioavailability of ModraDoc006, it is co-administered with ritonavir (/r). The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines The oral combination (ModraDoc006/r) was compared to IV docetaxel in a randomized phase 2b study in pts with mCRPC evaluating two doses of ModraDoc006/r (30-20/200-100 mg and 20-20/200-100 mg). Data on outcomes in the larger cohort, receiving the lower dose, are being presented. Methods: Eligible pts had mCRPC, performance status of 0-1 and no prior chemotherapy for mCRPC. Sixty-two pts were enrolled in open label 1:1 randomized study comparing ModraDoc006/r 20-20 mg combined with 200-100 mg ritonavir in a bi-daily weekly schedule (“20-20/200-100 mg”), with IV docetaxel 75 mg/m 2 in 21-day cycles. All pts received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives included ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Results: 31 pts were enrolled on IV docetaxel 75 mg/m 2 and 31 on ModraDoc006/r 20-20/200-100 mg. Of these, 57 were included in the analysis for rPFS, and 32 pts with measurable disease were included in the ORR analysis. Median PSA was 46 (range 1 to 1460 ng/ml). Prior therapy with enzalutamide in 8 pts, abiraterone in 10 pts. ModraDoc006/r was better tolerated with 0% all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% G1 only on ModraDoc006/r vs 9.7% G1 and 19.4% G2 on IV docetaxel, whereas alopecia was reduced to 16.1% G1 and 6.5% G2 on ModraDoc006/r vs. 22.6% G1 and 19.4% G2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥G3) vs 29%, nausea 29% vs 13% and stomatitis 3% (G3) vs 13% (3% ≥G3), respectively. Conclusions: ModraDoc006/r demonstrated a favorable safety profile and comparable efficacy to IV docetaxel in pts with mCRPC, thus providing a compelling rationale for conduct of an expanded pivotal program. A key clinical program focus is the comparison of ModraDoc006/r to best available therapy in refractory mCRPC. Studies of ModraDoc006/r in other malignancies are also in active development. Clinical trial information: NCT04028388. [Table: see text]
Sintilimab combined with chemotherapy in conversion therapy of advanced gastric cancer: A retrospective study.
Authors: Jingquan Fang, Xingmao Huang, Yang Cao, Zeyao Ye, Tengjiao Chai, Yian Du, Yu Pengfei
Journal: Journal of Clinical Oncology (2022)

e16012 Background: Gastric cancer is the fifth most common cancer in the world and the third leading cause of cancer death. At present, traditional chemotherapy is still the main treatment method of advanced gastric cancer, but the efficacy is limited. Immunotherapy has been identified as a treatment for chemotherapy-refractory gastric cancer, and sintilimab is a fully human IgG4 monoclonal antibody that binds to programmed cell death receptor-1 (PD-1). This study aims to investigate the efficacy of sintilimab combined with chemotherapy in patients with inoperable metastatic gastric cancer and analyze the prognostic factors of these patients. Methods: Patients with advanced gastric cancer which were initially treated unresectable and with distant metastasis in Zhejiang Cancer Hospital from August 2018 to December 2021 were retrospectively analyzed in this research. Patients received sintilimab combined with chemotherapy (PS regimen) ：sintilimab 200mg, day 1, paclitaxel was administered intravenously (150 mg/m 2 ) on day 1, and S-1 was administered orally (80 mg/m 2 /day) on days 1–14 of a 3-week cycle. The primary endpoints were treatment efficiency; and the secondary endpoint was safety and overall survival (OS) time. Results: A total of 66 patients were enrolled, including 43 males and 23 females, with an average age of 62.2 years (29-77 years). All of these patients had one or more distant metastases (liver 28 cases, peritoneum 20 cases, retroperitoneal lymph node 21 cases and ovary 5 cases). 33 patients (50%) underwent surgery, including conversion surgery (26 cases), palliative surgery (7 cases). The mean OS of patients with conversion surgery was 19.2 months (95%CI 16.5̃21.9 months), and the 2-year survival rate was 50.0%. The mean OS of non-conversion surgery was 16.9 months (95%CI 12.9̃20.1 months), and the 2-year survival rate was 29.1% (P=0.028). 24 (92.3%) cases had R0 resection. Multivariate analysis showed that postoperative CA125 level was an independent risk factor for prognosis of these gastric cancer patients. Conclusions: Sintilimab combined with chemotherapy is safe and effective, and combined with conversion surgery can improve the prognosis of patients with partially unresectable advanced gastric cancer.